1. Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists
- Author
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Marinozzi, Maura, Carotti, Andrea, Sansone, Emanuele, Macchiarulo, Antonio, Rosatelli, Emiliano, Sardella, Roccaldo, Natalini, Benedetto, Rizzo, Giovanni, Adorini, Luciano, Passeri, Daniela, De Franco, Francesca, Pruzanski, Mark, and Pellicciari, Roberto
- Subjects
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PYRAZOLES , *FARNESOID X receptor , *LUCIFERASES , *AZOLES , *ANTIPYRINE , *BENZOSELENADIAZOLE - Abstract
Abstract: A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy. [Copyright &y& Elsevier]
- Published
- 2012
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